ERK-Signaling in Microenvironment of Pancreatic cancer: Development of NovelTherapeutic Hypoxia-Responsive Nano-encapsulated ERK inhibitor

The Pancreatic ductal adenocarcinoma (PDAC), mostly a mutant K-Ras driven, in which hypoxia triggers
acidification of extracellular matrix, epithelial-to-mesenchymal transition (EMT)/cancer stemness (CSCs),
metastasis, desmoplasia, and chemoresistance. These pathological changes grim the prognosis of the disease.
Thus, EMT/CSCs and desmoplasia must be destructed to improve the prognosis. Emerging evidence indicates
that these processes are disrupted by targeting the extracellular signal-regulated kinases (ERKs) downstream
of the mutant K-Ras-signaling pathway. However, in the clinic, the weak bioavailability and dose-limiting toxicity
reduce ERK inhibitors' efficiency in halting tumor progression. Thus, there is a critical need to develop drug
carriers that selectively target PDAC tissues and suppress the growth of cancer cells via sustained drug release
deep into the tumor. We recently discovered that the efficacy of SCH 772984, an ERK-inhibitor (ERKi), can be
enhanced in systemic delivery if we encapsulated the ERKi in a pH/hypoxic-responsive nanocarrier (pHNPs)
attached with a tumor-penetrating peptide iRGD. Our preliminary studies suggest that ERKi suppresses the
production of CSCs and desmoplastic regulator protein CTGF/CCN2 in pancreatic cancer cells via blocking AP-
1-signaling. Finally, we also found that CTGF blockade by ERKi may participate in tumor fibroblast cell activation,
a hallmark of desmoplastic reaction. Building on these exciting preliminary findings, we propose finding the
optimal variant of ERKi-pHNPs, unraveling the mechanisms of response to ERKi therapy in human and murine
PDAC cell lines, and therapeutic efficacy alone or combined with gemcitabine and/or Nap-paclitaxel using
genetically engineered mouse models (GEMM) and Patient-derived xenograft (PDX) mouse models. The goal
of the project is to submit an investigational new drug application (IND) to the FDA with the long-term goal is to
translate this novel therapeutic product to the clinic to treat Veterans.
We propose three Aims. In Aim 1, we will synthesize different ERKi-pHNPs variants by modifying the
moieties, identifying an optimal variant from them by determining the in vitro and in vivo functional efficacy, and
evaluating the mechanism of action through the in vitro characterization in PDAC cells. In Aim 2, we will
determine the MTD, toxicity, and pharmacokinetics (PK) of an optimal variant of ERKi-PHNPs in the presence or
absence of chemotherapy in tumor-bearing CDX mice. Finally, in Aim 3, we will evaluate the effect of optimal
ERKi- pHNPs and free-GEM in translational studies using KPC and patient-derived tumor xenograft (PDX) models
for PC. The effect of Nab-paclitaxel with these combinations will also be tested. To realize these aims, we have
developed stimuli-responsive polymers (Mol. Pharmaceutics 2021, 18, 87−100 ), a unique in vitro desmoplastic
model (Mol Cancer Ther; 18, 2019), standardized non-invasive, high-resolution imaging, and high-thorough put
technologies to unveil various steps of tumor progression and associated molecular markers. We will use these
technologies and the outstanding collective expertise of our multi-disciplinary team to establish that ERKi-pHNPs
therapy is a powerful treatment strategy to target CSCs and desmoplasia and enhance the gemcitabine effect in
aggressive pancreatic cancer.

Grant Number: 5I01BX006279-02
NIH Institute/Center: VA
Principal Investigator: Sushanta Banerjee